We have recently demonstrated that new inner hair cells (IHCs) are generated in the mammalian organ of Corti following gene therapy. Specifically, the experiments involve in vivo inoculation of an adenovirus vector with the Math 1 gene insert into the mature predeafened guinea pig cochlea. We have also demonstrated that the new hair cells can attract neurons. Predeafend ears treated with Math 1 exhibit partial restoration of function as determined by Preyer's refex and significant improvement in acoustically-evoked auditory brainstem response (ABR) threshods. In the current application we propose to use animal-psychophysics techniques to define the nature and extent of the restored acoustic hearing. We will also conduct experiments relevant to the use of this gene therapy in conjunction with cochlear implants. Specifically, in Aims 1 and 2 we will deafen guinea pigs with ototoxic drugs, treat them with Math 1 and measure psychophysical detection and discrimination thresholds as well as ABRs. In Aim 3, we will assess the interaction between Ad.Math 1 inoculation, cochlear implantation, and electrical stimulation of the cochlear implant. In Aim 4 we will place a cochlear implant in the inoculated ear and assess psychophysical responses to electrical stimulation with and without restored IHCs. The experiments we propose involve the use of techniques that are already in place in our laboratories. The work is backed by strong preliminary data, and represents an ideal combination of relatively low-risk with very high impact. The proposed experiments will bring this gene therapy application closer to clinical use.